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(Circulation. 1997;96:778-784.)
© 1997 American Heart Association, Inc.
Articles |
C-Reactive Protein as a Predictor of Infarct Expansion and Cardiac Rupture After a First Q-Wave Acute Myocardial Infarction
From the Cardiopulmonary Division, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
Correspondence to Toshihisa Anzai, MD, Cardiology Section (9111A), Department of Veterans Affairs Medical Center, University of California, San Diego, 3350 La Jolla Village Dr, San Diego, CA 92161. E-mail tanzai{at}vapop.ucsd.edu
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Abstract |
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Background Pump failure after acute myocardial infarction (AMI) can be predicted by several indices that estimate infarct size. However, there are few indices that predict infarct expansion and cardiac rupture. We focused on the prognostic significance of serum C-reactive protein (CRP) after AMI.
Methods and Results Serum CRP levels were measured every 24
hours in 220 patients with a first Q-wave AMI. In-hospital
complications, predischarge left ventriculographic findings, and
long-term prognosis were assessed in relation to peak CRP levels. Peak
levels of both CRP and creatine kinase (CK) were higher in patients
with pump failure than in those without pump failure. In patients with
cardiac rupture, peak CRP levels were higher than in those without
rupture (P=.001); peak CK levels were not predictive. Higher
CRP levels were found in patients with left ventricular
aneurysm (P=.001 versus those without), aggravated
heart failure (P=.03 versus those without), and cardiac
death (P<.0001 versus survivors) during the first year
after AMI. Multivariate analysis confirmed that
an elevation of the peak CRP level 
20 mg/dL was an independent
predictor of cardiac rupture (relative risk, 4.72; P=.004),
left ventricular aneurysmal formation (relative
risk, 2.11; P=.03), and 1-year cardiac death (relative risk,
3.44; P<.0001).
Conclusions Cardiac rupture, left ventricular aneurysmal formation, and 1-year cardiac death were associated with an elevation of serum CRP early after AMI, suggesting that elevation of CRP levels after AMI may predict infarct expansion.
Key Words: proteins • aneurysm • myocardial infarction
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In patients who suffer an acute myocardial infarction (AMI), cardiac rupture is the second most common cause, after pump failure, of in-hospital death.1 2 Cardiac rupture usually occurs unexpectedly and is almost always fatal. AMIs complicated by cardiac rupture are usually transmural, but the infarct size is variable.3 Its occurrence is still difficult to predict by the previously reported risk factors,4 5 6 7 8 whereas pump failure can be predicted using several indices that estimate infarct size. If cardiac rupture is recognized early, the mortality rate can be reduced considerably by appropriate preparations for surgical repair.
Cardiac rupture is an extreme form of infarct expansion during the early phase of an AMI.9 10 Defective infarct healing, as well as left ventricular wall stress, plays a major role in infarct expansion and may play an important role in the development of cardiac rupture.11 There is evidence that methylprednisolone,12 indomethacin,13 and ibuprofen14 induce scar thinning and infarct expansion in the setting of experimental infarction, and the use of these anti-inflammatory agents is associated with increased incidence of cardiac rupture in humans.15
C-reactive protein (CRP) is a nonspecific, commonly used marker for acute inflammatory response. Inflammatory cells release cytokines, which stimulate hepatocytes to release CRP.16 A previous report suggested that peak serum interleukin-6 levels in patients with an AMI correlated well with peak serum CRP levels, whereas there was no direct relation between peak interleukin-6 levels and peak creatine kinase (CK) activity.17 It is possible that the serum CRP level reflects the process of infarct healing rather than the extent of myocardial necrosis. However, the prognostic significance of serum CRP level elevation after an AMI remains unexplored. We hypothesized that the serum CRP level could be used to predict infarct expansion resulting in cardiac rupture. The primary aim of this study was to determine the short- and long-term prognostic significance of the serum CRP level regarding infarct expansion and cardiac rupture after a first Q-wave AMI.
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Methods |
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Study Population
A total of 324 consecutive patients experiencing their first Q-wave AMI were examined. Serial measurements of serum CRP level every 24 hours were performed. Patients in whom peak CRP levels could not be determined by late admission (n=57) or death in early phase (n=14) were not eligible in this study. In addition, the patients with collagen disease, advanced liver disease, renal failure, malignant diseases, septicemia, or other infectious diseases were excluded from this study population (n=33). Finally, 220 patients were eligible to participate in this study (age range, 19 to 98 years; mean, 62 years). The patients were admitted to Keio University Hospital between May 1985 and March 1995, within 24 hours of onset of AMI. A diagnosis of Q-wave AMI was established as described previously.18 Infarction sites were assessed as follows: anterior wall: patients with new abnormal Q waves in at least two adjacent precordial leads (n=133); inferior wall: in leads II, III, and aVF (n=75); and lateral wall: in leads I and aVL (n=12). Patients in whom peak CRP levels could not be determined include 4 with cardiac rupture and 14 with in-hospital death. However, the incidence of cardiac rupture (4% versus 4%, P=.9) and in-hospital mortality (10% versus 13%, P=.2) was not different between the patients who were eligible and those who were not eligible. None of the patients had a prior history of myocardial infarction. Informed consent was obtained from each patient. This study protocol was in agreement with the guidelines of the ethics committee of our institution.
Study Protocol
Venous blood samples were obtained on admission to the hospital,
every 6 hours until the peak CK level was determined, and then every 24
hours for at least 4 days. Serum samples were stored at -70°C and
were later analyzed to determine CK and CRP levels. CRP levels
were measured by latex photometric immunoassay (LPIA-CRP, Mitsubishi
Chemical, Inc) with the use of an autoanalyzer (Hitachi
7450).
The following data were obtained: age, sex, presence of coronary risk factors (cigarette smoking, hypertension as defined by the Joint National Committee V,19 diabetes mellitus as defined by the WHO Study Group,20 hypercholesterolemia, and cholesterol level >220 mg/dL), history of preinfarction angina, use of and success rate of revascularization therapies during the early phase of myocardial infarction, incidence of complications, and in-hospital mortality rate. Pump failure was defined as a grade of class 2 or greater according to Killip's classification21 or greater than subset II according to Forrester's classification.22 Cardiac rupture included free wall rupture and ventricular septal perforation. The diagnosis of free wall rupture was confirmed by echocardiographic study followed by pericardiocentesis, surgery, or postmortem examination. Ventricular septal perforation was diagnosed in the presence of both abnormal shunt flow at interventricular septum on color Doppler echocardiographic study and significant step-up of oxygen saturation at the right ventricle.7 Postinfarction pericarditis was diagnosed if the typical pericardial friction rub was heard on examination by the patient's supervising physician.
Follow-up data including the number of readmissions for heart failure, presence of unstable angina, episodes of recurrent myocardial infarction, history of percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass graft surgery (CABG), and cardiac deaths including sudden death within 1 year from the onset of AMI were obtained through direct contact at an outpatient clinic or by a mail interview in patients who survived the AMI. The incidence of postdischarge ischemic events was also assessed, defined as unstable angina requiring readmission, recurrent myocardial infarction, or receiving PTCA or CABG.
Angiographic Analysis
Selective coronary angiography was performed with the
use of multiple projections. The degree of coronary artery
stenosis was determined by caliper method and classified
according to the American Heart Association system.23
Significant angiographic coronary artery stenosis was
defined as a narrowing >75%. Successful reperfusion was defined as
TIMI grade 2 or more in the infarct-related coronary
artery.24 Global left ventricular ejection
fraction and end-diastolic left ventricular
volume were estimated from the right anterior oblique projection of
the contrast left ventriculography during convalescence according to
the method of Kasser and Kennedy.25 Left
ventricular aneurysms were assessed from both the
right and left anterior oblique views. Left ventricular
aneurysm was considered to be present only if all the
following criteria described by Meizlish et al26 were met:
the presence of a well-localized region of the left ventricle
exhibiting either akinesis or dyskinesis, a discrete deformity
occurring in both systole and diastole, and a normally
contractile segment of myocardium adjacent to the area of
regional dysfunction.
Statistical Analysis
Data are expressed as mean±SD. Comparison between two groups
was performed with the use of an unpaired t test or a
nonparametric means test. Differences in prevalence were
compared with the use of the 
2 test. Multiple
logistic regression analysis was used to assess the effect of
various factors on cardiac rupture or development of left
ventricular aneurysm. Long-term prognosis including
1-year cardiac mortality after the onset of AMI was assessed by Cox
proportional hazards model. To determine the cut-point of the peak CRP,
receiver operating characteristic analysis was performed.
Statistical significance was defined as a value of
P<.05.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Patient Characteristics and Peak CRP Levels
For the entire study population, the mean peak CRP level was 14.1±11.3 mg/dL (n=220). The mean elapsed time from the onset of an AMI to the time of the CRP peak was 3±2 days. Older age (
70
years), absence of preinfarction angina, and angiographically failed
revascularization therapies were associated with
higher peak CRP levels (Table 1
).
Revascularization therapies were less commonly
performed in older patients (70 years) than in younger patients (27%
versus 48%, P=.0006). The success rate of
revascularization therapies was the same in older
and younger patients (88% for both groups).
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Relations Between Peak CRP and CK Levels
Peak CRP levels showed a weak positive correlation with peak CK
levels (r=.27, P=.0004). The correlation was
weaker in patients with (r=.25, P=.02) than in
those without revascularization therapies
(r=.55, P<.0001). In patients with
angiographically successful revascularization
therapies, the correlation was not significant (r=.17,
P=.18).
In-Hospital Complications and Serum Peak CRP and CK Levels
Table 2 shows the relation between the presence or absence of
complications after AMI and peak CRP
levels. Peak CRP levels were
higher in patients with pump failure than in those without pump
failure. Similarly, peak CK levels were also higher in patients with
than in those without pump failure (2681±1678 versus 1620±1505 IU/L,
P<.0001). Cardiac rupture was diagnosed at 4±2 days after
the onset of myocardial infarction. Peak CRP levels in patients with
cardiac rupture were higher than in those without rupture, whereas no
significant difference was noted in peak CK levels (2808±1655 versus
1875±1614 IU/L, P=.20). The time from the onset to peak CRP
in the patients with cardiac rupture was similar to that in the
patients without cardiac rupture (3±2 versus 3±1 days,
P=.79).
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Fig 1 shows the typical time course of serum CRP and CK levels in an
uncomplicated patient and in a patient with free wall rupture after
anterior wall AMI. Both of the
patients did not undergo any revascularization
therapies. In the patient with cardiac rupture, there was a
disproportionate elevation of serum CRP levels compared with serum CK
levels. There was no significant difference between the peak CRP levels
of patients with free wall rupture and patients with
ventricular septal perforation (21.4±4.2 versus 25.5±2.9
mg/dL, P=.13).
|
Peak CRP levels in patients with postinfarction pericarditis were higher than those in patients without pericarditis (23.9±8.5 versus 12.3±10.5 mg/dL, P=.004). Four patients with pericarditis also suffered pump failure, but none was complicated by cardiac rupture or in-hospital cardiac death.
In patients with in-hospital cardiac death, both peak CRP levels and
peak CK levels (2987±1625 versus 1823±1594 IU/L, P=.01)
were higher than those in the survivors (Table 2
).
Angiographic Findings
Coronary arteriography was performed in 161 patients
(73%) a mean of 9 days after the onset of AMI. Peak CRP levels were
similar in patients with and in those without multivessel
coronary artery disease (11.3±9.7 versus 10.6±8.7
mg/dL, P=.60). Left ventriculography was performed in
101 patients (46%) during convalescence, a mean of 12 days after the
onset of infarction. Peak CRP levels correlated positively with left
ventricular end-diastolic volume and inversely
with ejection fraction. Similarly, peak CK levels correlated inversely
with ejection fraction. However, there was no significant correlation
between peak CK levels and end-diastolic volume (Fig 2). In patients who did not undergo
reperfusion therapy, the correlation between peak CK levels and
end-diastolic volume was also not significant
(r=.26, P=.11).
|
The presence of a left ventricular aneurysm was
associated with higher peak CRP levels (14.4±10.0 versus 7.7±6.8
mg/dL, P=.0002) as well as with higher peak CK levels
(3227±1634 versus 1670±1899 IU/L, P=.001) (Table 2).
Long-term Prognosis
Of the 220 patients, 88% (n=194) were followed for >12 months.
The average follow-up period is 36 months. Peak CRP levels in patients
who readmitted with heart failure were higher than in those without
heart failure. The presence of postdischarge ischemic events
was associated with lower peak CRP levels. Peak CRP levels were higher
in patients who suffered an out-of-hospital cardiac death during the 12
months after AMI than survivors (Table 2). In patients with 1-year
cardiac death including in-hospital death, peak CRP levels were also
higher than those in survivors (26.4±12.1 versus 11.0±9.2
mg/dL, P<.0001).
Determinants of Cardiac Rupture, Aneurysmal
Formation, and 1-Year Cardiac Mortality
Fig 3 shows the receiver operating characteristic analysis
to determine the cut-point of peak CRP level as a predictor of cardiac
rupture and 1-year cardiac death. The
cut-point of 20 mg/dL was selected as a predictor because of the
high sensitivity and specificity to predict the both complications.
Multiple logistic regression analysis showed that a peak CRP
level 20 mg/dL was the strongest predictor of cardiac rupture
and left ventricular aneurysmal formation, compared
with other variables including age 70 years old, use of
revascularization therapies, and anterior site of
myocardial infarction. Older age was also an independent predictor of
cardiac rupture. Anterior site of myocardial infarction was an
independent predictor of ventricular aneurysmal
formation but was not a significant predictor of cardiac rupture (Table 3). Cox proportional hazards
analysis was performed to assess the end points at 1 year from
the onset of myocardial infarction. It showed that a peak CRP level
20 mg/dL was a strong independent predictor of 1-year cardiac
death (Table 4). Aggravated heart failure
after discharge was observed only in 5 patients. The Cox proportional
hazards analysis did not show a significant predictor for
aggravated heart failure after discharge among these four
variables. As a predictor of ischemic events including
readmission with unstable angina, reinfarction, PTCA, or CABG, anterior
site of the infarction was a predictor, whereas other variables
were not significant. Peak CRP level 20 mg/dL, as well as age
70 years old, was a significant predictor for all in-hospital and
out-of-hospital events including in-hospital pump failure or
out-of-hospital heart failure, cardiac rupture, ischemic
events, and cardiac death (Table 4).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The present study has demonstrated that the peak serum CRP level was a powerful short-term and long-term prognostic indicator after a first Q-wave AMI. The presence of preinfarction angina, successful revascularization therapies, and younger age was associated with lower peak CRP levels. A disproportionate elevation of serum CRP levels, compared with CK levels, was observed in patients with cardiac rupture. Elevation of the CRP level
20
mg/dL was a major independent predictor of cardiac rupture,
ventricular aneurysmal formation, and cardiac death
during the year after a first Q-wave AMI. There are several studies showing that serum CRP levels increase during an evolving myocardial infarction.27 28 29 30 CRP is produced in hepatocytes by the stimulation of various cytokines, including interleukin-6, tumor necrosis factor, and interleukin-1. These cytokines are released from monocytes/macrophages activated by the ischemic injury process in an AMI.31 Recent evidence suggests that plasma interleukin-6 levels closely correlate with serum CRP levels in patients with AMI.32 In large populations with AMI, CRP is a more commonly measured marker than are such cytokines. However, there are few reports on the significance of serum CRP measurement in the pathophysiology of AMI.33 34
Several studies have focused on the relationship between serum CRP level and infarct size, but the results were inconsistent.17 32 33 34 35 Pietila et al35 assessed the relation between peak CRP and CK levels in patients who received reperfusion therapy compared with those who did not in a relatively large population of patients. They found that the correlation between peak CRP levels and concentration-time integrals of the CK levels was weaker in patients with successful reperfusion than in those without successful reperfusion. In our study, there was a significant correlation between serum peak CRP and CK levels, especially in patients without revascularization therapies. In patients in whom successful reperfusion was achieved, the correlation was not significant. The washout effect of CK from the reperfused myocar-dium may be in part responsible for the abolition of the relation,36 although other explanations remain possible because the correlation between peak CRP levels and concentration-time integrals of the CK levels was still weak in patients with successful reperfusion.35
CRP levels were higher in elderly patients than younger patients. One of the reasons may be that revascularization therapies, which are potentially associated with lower serum CRP levels, were more commonly performed in younger patients than elderly patients. In fact, CRP levels were lower in patients in whom revascularization was successful than those in whom it failed.
Preinfarction angina was another factor influencing CRP levels. Our previous studies showed that the presence of preinfarction angina appeared to have a beneficial effect on left ventricular function and on short- and long-term prognosis by limiting infarct size through unidentified mechanisms other than collateralization.37 38 The limitation of infarct size in the presence of preinfarction angina may account for the lower peak CRP levels.
Previous reports have studied CRP levels in various populations of patients with AMI, including patients with or without prior infarction and with or without thrombolytic therapy.17 32 According to Pietila et al,39 serum CRP levels do not rise in patients with certain non–Q-wave infarctions. In patients with prior infarction, it is difficult to determine the significance of serum CRP levels in the pathophysiology of AMI, especially regarding pump failure, changes in ventricular function, and long-term prognosis. Accordingly, we excluded patients with prior infarction and with non–Q-wave infarction from the analysis in this study.
Previous studies have failed to clearly characterize the significance of the serum CRP level in the pathophysiology of AMI. Pietila et al34 demonstrated that serum CRP levels were higher in patients with cardiac failure than those without cardiac failure. Our study has confirmed this finding in a larger study population. The outstanding finding of our study was that serum CRP levels but not CK levels were higher in patients with cardiac rupture, which has been difficult to predict with the use of other conventional tests. Cardiac rupture can be precipitated by infarct expansion, which, in turn, is influenced by infarct healing and wall stress.9 10 This complication usually occurs during the first week after a transmural infarction when the necrotic myocardium is vulnerable to wall stress.9 During this period, pathological specimens show a central core of necrotic myocardium surrounded by a zone of hemorrhage and acute inflammation.40 Ross and Young41 have reported that the degree of polymorphonuclear infiltration in the area of myocardial infarction could be correlated with the incidence of cardiac rupture. Severe inflammation resulting in tissue vulnerability is a possible cause of the extreme elevation in serum CRP level in patients with cardiac rupture. Serum CRP levels were higher in patients with pericarditis than in those without pericarditis. This increase in the CRP level does not account for the higher CRP levels in patients with cardiac rupture because none of the patients with pericarditis also suffered a cardiac rupture. However, it could not be completely excluded that subclinical pericarditis preceded the occurrence of cardiac rupture. Another limitation of this study was that peak CRP level could not be determined in patients with death in the superacute phase, including acute cardiac rupture. Although the incidence of cardiac rupture was not different between patients who were eligible in this study and those who were not, the prediction of cardiac rupture by peak CRP levels could be used only in patients who survived the superacute phase, and the serum CRP levels measurement might be of significance in predicting subacute cardiac rupture.
One study showed that there was an inverse correlation between serum CRP level and left ventricular ejection fraction in both patients who underwent recanalization therapy and those who did not.35 In our present study, left ventricular end-diastolic volume closely correlated with serum CRP levels but not with serum CK levels, although ejection fraction correlated with both CRP and CK levels. Washout effect of the serum CK could not completely explain this phenomenon because the result was essentially similar in patients who did not undergo reperfusion therapy.
Left ventricular aneurysms occur with the long-term
form of infarct expansion,42 whereas cardiac rupture is an
extreme form of acute infarct expansion. We showed that a higher peak
CRP level (20 mg/dL) was an independent predictor of both
cardiac rupture and left ventricular aneurysmal
formation. These findings suggest that the peak CRP level is a strong
predictor of infarct expansion, reflecting both infarct size and
infarct healing.
None of the prior studies evaluated the prognostic significance of the
serum CRP level in patients with an AMI except for one study in which
there was no difference in CRP levels between survivors and
nonsurvivors in 19 patients with an AMI.43 In our
present study, peak CRP levels were higher in patients with
aggravated heart failure after hospital discharge than in those without
heart failure. Multivariate analysis revealed
that an elevation of the CRP level 20 mg/dL was an independent
predictor of cardiac mortality during the first 12 months after a first
Q-wave AMI. Previously, Meizlish et al26 reported that
left ventricular aneurysmal formation was
associated with a high mortality rate during the first 12 months after
infarction and that this risk was independent of left
ventricular ejection fraction. The infarct expansion seen
in patients with aneurysmal formation is a major part of the
left ventricular remodeling that is known to be related to
their long-term prognosis after an AMI.44 45 In this
regard, peak CRP level could be an independent indicator of infarct
expansion and long-term prognosis.
Received December 16, 1996; revision received February 19, 1997; accepted February 24, 1997.
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T. Katayama, H. Nakashima, Y. Honda, S. Suzuki, and K. Yano Relationship Between Adrenomedullin and Left-Ventricular Systolic Function and Mortality in Acute Myocardial Infarction Angiology, January 1, 2005; 56(1): 35 - 42. [Abstract] [PDF]
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L. M. Biasucci CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: Clinical Use of Inflammatory Markers in Patients With Cardiovascular Diseases: A Background Paper Circulation, December 21, 2004; 110(25): e560 - e567. [Abstract] [Full Text] [PDF]
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H. R. Chandra, J. A. Goldstein, N. Choudhary, C. S. O'Neill, P. B. George, S. R. Gangasani, L. Cronin, P. A. Marcovitz, A. M. Hauser, and W. W. O'Neill Adverse outcome in aortic sclerosis is associated with coronary artery disease and inflammation J. Am. Coll. Cardiol., January 21, 2004; 43(2): 169 - 175. [Abstract] [Full Text] [PDF]
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C. B. Granger, K. W. Mahaffey, W. D. Weaver, P. Theroux, J. S. Hochman, T. G. Filloon, S. Rollins, T. G. Todaro, J. C. Nicolau, W. Ruzyllo, et al. Pexelizumab, an Anti-C5 Complement Antibody, as Adjunctive Therapy to Primary Percutaneous Coronary Intervention in Acute Myocardial Infarction: The COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) Trial Circulation, September 9, 2003; 108(10): 1184 - 1190. [Abstract] [Full Text] [PDF]
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M. R. Cusack, M. S. Marber, P. D. Lambiase, C. A. Bucknall, and S. R. Redwood Systemic inflammation in unstable angina is the result of myocardial necrosis J. Am. Coll. Cardiol., June 19, 2002; 39(12): 1917 - 1923. [Abstract] [Full Text] [PDF]
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